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Fisetin—a new senolytic

Senolytic drugs have been the most promising near-term anti-aging therapy since the ground-breaking paper by van Deursen of Mayo Clinic published in 2011. The body accumulates senescent cells as we age, damaged cells that send out signal molecules that in turn modify our biochemistry in a toxic, pro-inflammatory direction. Though the number of such cells is small, the damage they do is great. Van Deursen showed that just getting rid of these cells could increase lifespan of mice by ~25%. But he did it with a trick, using genetically engineered mice in which the senescent cells had a built-in self-destruct switch.

After that, the race was on to find chemical agents that would do the same thing without the genetically engineered self-destruct. They must selectively kill senescent cells, while leaving all other cells unharmed. It’s a tall order, because even a little residual toxicity to normal cells can be quite damaging. Before last week, the two best candidates were FOXO4-DRI and a combination of quercetin with dasatinib.

I’ve written in the past (here and here) that senolytic drugs are our best prospect for a near-term lift on the road to anti-aging medicine.

Last week, a large research group affiliated with the original May Clinic team published findings about fisetin, the latest and greatest candidate for a senolitic pill, another flavenoid, very close in structure to quercetin.

They grew senescent and normal cells in a test tube, then tested 11 different plant-derived chemicals for power to kill the one while leaving the other unharmed. The winner was fisetin.

(MEF stands for Mouse Embryonic Fybroblast, the cells that were cultured in the screening experiment.)

Fisetin is especially interesting because it is cheap, easily available, widely-regarded as safe, but not nearly as well studied as quercetin.

They took the winner, fisetin, and subjected it to a series of tests. They began with in vitro (cell culture) tests and proceeded to in vivo tests with live animals, culminating with an impressive life span assay in mice.

(The runner-up was curcumin, less interesting perhaps only because it has already been extensively studied. The curcumin molecule is unrelated to quercetin or fisetin, and is not a flavenoid. I can’t help but wonder if they had subjected curcumin to the same thorough testing that they reserved for fisetin, how would curcumin have fared?)

curcumin

The paper’s principal findings were:

Fisetin has lower liver toxicity (at equivalent doses for senolytic benefit) than any of the other senolytics tested so far.

Fisetin reduces pro-inflammatory signaling in a short course given to mice and in long-term experiments where fisetin was added to the mouse chow.

Fisetin reduces number of senescent fat cells in a short course given to mice.

Mice fed fisetin for long periods had much more glutathione than control mice. (Glutathione is one of very few marker molecules that seems to be wholly beneficial.)

Most impressively, mice fed fisetin late in life lived 10-15% longer than control mice. This represents a 50% increase in the remaining lifespan after the intervention.

What we know and what we’d really like to know

We’d like to know, do humans who take large doses of fisetin live longer? Do they have toxic side-effects? These questions require decades to answer.

Does fisetin reduce age markers in humans, especially methylation age? This is a feasible study, since the test is mature and safety of fisetin is fairly well established for short courses. Perhaps this experiment is being considered; I’ve written to the corresponding authors of the most recent study, in case they haven’t already thought of it. This test would not be definitive because we know that methylation age is not perfectly correlated with biological age; but if positive it would confirm both that fisetin is accomplishing epigenetic rejuvenation and that methylation tests were correctly informing us of this; a negative result would be ambiguous.

Episodic Dosing

It makes sense that senolytics should be taken periodically, not continuously. A high dose can be toxic to existing senescent cells, and then getting out of the way, it can allow normal cells to recover from any damage. This sounds like good theory, but different dosing regimens have not been tested experimentally. In fact, the new paper reports positive results from both high episodic dosing and lower everyday dosing.

The Mayo group had previously tested fisetin, and found it effective in killing some kinds of human senescent cells but not others. In previous tests, fisetin was found to be effective in senescent fat cells (pre-adipocyte, white adipose tissue), and that is where it was primarily tested in the new studies.

Authors’ comments

They note that the episodic treatment and short half-life suggest that the benefits of fisetin come from its senolytic action, rather than other actions as an antioxidant and signal molecule. They emphasize that clearing senescent white blood cells and making room for new, active white blood cells are activities that enhance the benefits of fisetin, since white blood cells contribute to clearing the remaining senescent cells.

If we choose to take fisetin at this stage in the science, we are early adopters, and our main concern ought to be safety. There is little doubt that killing senescent cells will be beneficial. But what is the toxic burden of fisetin, and what dosage can we safely take without risk of damage to normal cells? The current study covers a lot of ground but doesn’t answer this question, apparently because they are convinced that fisetin is quite safe.

Strawberries, apples, grapes, and onions all contain fisetin, but at low levels compared to a senolytic dose. For example, the highest food concentration, 160 ppm, is found in strawberries. A half pound of strawberries yields 36 mg of fisetin. We’re still guessing at the therapeutic dose, based on mouse studies, and the experimental dosage in human trials is about 1,000 to 1,500 mg (based on this clinical trial), the content to 30-40 pounds of strawberries on each of two consecutive days.

In the best cases, fisetin was shown to reduce senescent cell burden by 50% and up to 75% in cell cultures. This is a good start, and encourages us to think we can do better by combining fisetin with other agents, or perhaps with fasting.

It sounds impressive, but I’m not impressed. First, mouse models of Alzheimer’s have been discredited repeatedly. Mice don’t naturally get AD, so they have to be genetically engineered to do so, and the genetically modified mice don’t share the deep causes of human AD. Time and again, treatments have been found effective in the mouse model that fail to translate to humans. Second, the treatment used in the study to kill senescent brain cells also relied on another genetic modification, and would not be applicable to humans.

My guess is that effective senolytic agents for humans will be available within a few years, and that they will decrease risk of all age-related disease, including Alzheimer’s. But this study does little to advance us toward that goal.

Thank you once again for sharing the news, Josh! I’m thinking that another thought in considering episodic rather than everyday dosing of fisetin (or many other supplements) is the former protocol’s greater potential to diminish a homeostatic response, which may in turn diminish these supplements’ effectiveness. Any other thoughts on this?

It’s true I would be tempted to eat more strawberries if it can rejuvenate me even a bit. But there is a nagging question: What happens when a senescent neuron or a senescent cardiac pacemaker cell dies?

Neurons don’t divide, so they don’t go senescent from short telomere length… but senescent cells don’t perform their normal functions correctly anyway. The senescent fibroblasts that I nursed along for a couple of years blew up to 10X the right size… and they spew pro-inflammatory chemicals.

In case my last post failed because of containing a link. Good coverage of fisetin. Perhaps another ‘natural senolytic’ is piperlongumine (from Indian long pepper). An article on Pubmed describes one mechanism — title is “Oxidation resistance 1 is a novel senolytic target.”

Melatonin suppresses doxorubicin-induced premature …https://www.ncbi.nlm.nih.gov/pubmed/22536785
Together, these results reveal that melatonin has an inhibitory effect of melatonin on premature senescence at the cellular level and that melatonin protects A549 cells from DOX-induced senescence. Thus, melatonin might have the therapeutic potential to prevent the side effects of …

Jeff – you provide excellent information and I enjoy reading your posts.
Thank you for the contribution – I was only joking about your vast over-simplification of Bredesen’s supplement/protocol anti-alzheimer’s regimen (55 items listed) as possibly down to just 1 supplement: melatonin (which is obviously ridiculous).
I think melatonin is beneficial but certainly not the panacea you make it out to be; but if it helps you sell books, carry on.

I noticed an interesting exclusion criterion in Dr. Kirkland’s clinical trial, i.e. the concomitant use of proton pump inhibitors. I assume that has to do with the ability of these drugs to inhibit the ABC transporters and increase absorption of polyphenols as described in this interesting paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820202/. I suppose that the extent of the effect is imprecisely known thus far, and would therefore muddy the results. Still, this has the potential to facilitate entry of polyphenols to various tissues, such as the brain, so that more types of senescent cells could potentially be targeted. I hope to encounter more research on this. Does anyone know of any, or have thoughts on the matter?

Josh, regarding your idea of testing epigenetic age changes from a senolytic therapy – I think the result would depend on the tissue type. If the cleared cells were then replaced by differentiation from epigenetically younger stem cells then you would expect a positive result. But in some cases cells are turned over very rapidly anyway, and I’m that case I expect an ambiguous result.

Didn’t they show epigenetic age reversal for allogenic stem cell transplant patients?

My major concern about Fisetin is that it acts as a topoisomerase 1 and 2 inhibitor. Various chemotherapy drugs also work via this mechanism and have to found to damage chromosomes and may lead to leukemia, in particular AML.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961513/

It has also been recently demonstrated that this same mechanism may lead to the tendon ruptures seen with certain antibiotics in the fluoroquinolone class.

The inhibition of topoisomerase 1and 2 is a real concern with Fisetin, especially at high doses.

Paul, this is very interesting. I had no idea fisetin had these powerful properties. As for topoisomerase 2 inhibitors like fluoroquinolones, they should not exert a negative effect on human cell lines (at least in theory), because the affected bacterial enzymes have little homology with mammalian DNA gyrase. The tendon rupture issue remains elusive, but the underlying cause seems to be related to fluoroquinolones toxicity to type 1 collagen.

Cipro impairs mitochondrial energy production and blocks cellular differentiation most likely leading to most of its side effects including tens rupture. This is most likely due to topoisomerase 2 inhibition. Normal doses of Fisetin are of no concern, but the very high dosing may well be a problem. https://www.sciencedaily.com/releases/2018/10/181001101943.htm

Not to mention the association of topoisomerase 1 and 2 inhibition with the development of AML.

Fisetin may be perfectly safe at any dose. We’ll see. But I’m going to wait until we know more.

Thanks for the heads up, Paul. So now I’m thinking we should wait for the results of the clinical trials before we start messing around with fisetin.

On the other hand, I’m not a very patient person, and, at 52, I’m starting to feel the effects of all these goddamned senescent rabble-rousing freeloaders in all my tissues, so I’ll happily spend some energy trying to find a cheat. Some questions that come to mind:

1) What are the plasma levels at which fisetin has significant senolytic activity, and how do these compare with the levels that mess with topoisomerase?

2) Are the deleterious effects of topoisomerase inhibition limited to rapidly proliferating cells and, if so, what happens to the proliferation rates of these cell types during a fast? Might we be able to mitigate the consequences by taking fisetin during a fast? (I know that leukocytes multiply quickly on refeeding _after_ a fast (see V. Longo), so presumably that would be a bad time to use fisetin.)

3) Would a combination of fisetin and curcumin synergize to produce useful senolytic effects while keeping fisetin concentrations low enough to be safe?

Cellular senescence can be terminated via two distinct methods. one by causing the cell to undergo apoptosis and the other is to regress or resque the cell from senescence by reverting or restoring the health of the cell back to a fully functional cell. I am not sure the researchers have said which mechanism or both are at play here?

I find it interesting that fisetin as researched by Salk institute over the last 10 years is a powerful antioxidant that increases glutathione levels over time. Also they have shown fisetin to have anticancer and antidiabetic effects.

The question is does fisetins antioxidant effects cause senescent cells to be rescued from senescence to the point that they become apoptosis-competent and then eliminate themselves? Or does the antioxidant effects of fisetin even go further with some senescent cell and allow the cell to repair itself enough to become fully functioning again and not undergo apoptosis?

Does fisetin sort of resurrect the ( now considered dead ) free radical theory of aging?

Abstract
Abstract Image
Recent data suggest that curcumin, a phytochemical with cancer chemopreventive potential, might be useful in the treatment of several solid and hematological malignancies. DNA topoisomerases (topos) are the target of several drugs commonly used in cancer chemotherapy. These drugs induce topo−DNA complexes with either topo I or topo II; then cellular processing converts these complexes into permanent DNA strand breaks that trigger cell death. Using the TARDIS in vivo assay, this study shows for the first time that curcumin induces topo I and topo II (α and β)−DNA complexes in K562 leukemia cells. A comparative analysis revealed that the levels of these complexes were higher than those induced by several standard topo I and topo II inhibitors at equitoxic doses. Curcumin-induced topo I and topo II−DNA complexes were prevented by the antioxidant N-acetylcysteine; this suggests that, unlike the standard topo inhibitors, reactive oxygen species may mediate the formation of these complexes. Overall, this work shows that curcumin is capable of inducing topo−DNA complexes in cells with both topo I and topo II and increases the evidence suggesting that this dietary agent has potential to be tested in cancer
chemotherapy

and another one

Antagonism between curcumin and the topoisomerase II inhibitor etoposide
A study of DNA damage, cell cycle regulation and death pathways
Ekram M. Saleh, 1 , † * Raafat A El-awady, 2 , 3 , † Nadia A. Eissa, 4 and Wael M. Abdel-Rahman 5
Author information Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Go to:
Abstract
The use of combinations of chemotherapy and natural products has recently emerged as a new method of cancer therapy, relying on the capacity of certain natural compounds to trigger cell death with low doses of chemotherapeutic agents and few side effects. The current study aims to evaluate the modulatory effects of curcumin (CUR), Nigella sativa (NS) and taurine on etoposide (ETP) cytotoxicity in a panel of cancer cell lines and to identify their underlying mechanisms.

CUR alone showed potent antitumor activity, but surprisingly, its interaction with ETP was antagonistic in four out of five cancer cell lines. Neither taurine nor Nigella sativa affect the sensitivity of cancer cells to ETP. Examination of the DNA damage response machinery (DDR) showed that both ETP and CUR elicited DNA double-strand breaks (DSB) and evoked γ-H2AX foci formation at doses as low as 1 µg/ml. Cell cycle analysis revealed S phase arrest after ETP or CUR application, whereas co-treatment with ETP and CUR led to increased arrest of the cell cycle in S phase (MCF-7 cells) or the accumulation of cells in G2/M phases (HCT116, and HeLa cells). Furthermore, cotreatment with ETP and CUR resulted in modulation of the level of DNA damage induction and repair compared with either agent alone. Electron microscopic examination demonstrated that different modalities of cell death occurred with each treatment. CUR alone induced autophagy, apoptosis and necrosis, whereas ETP alone or in combination with CUR led to apoptosis and necrosis.

Conclusions: Cotreatment with ETP and CUR resulted in an antagonistic interaction. This antagonism is related, in part, to the enhanced arrest of tumor cells in both S and G2/M phases, which prevents the cells from entering M-phase with damaged DNA and, consequently, prevents cell death from occurring. This arrest allows time for the cells to repair DNA damage so that cell cycle -arrested cells can eventually resume cell cycle progression and continue their physiological program.

I pattern my week with a 4 day protein fasting period followed by a protein feasting period. I try to time my workouts and supplements around this pattern, but I’m still in the process of figuring it out. My 2 strength training weekly workouts bookend each transition, with a HIIT workout during the protein fast. I also plan on a complete fast maybe once a quarter, but have only managed to complete one about 8 months ago. Planning is easy, doing not so much as life happens. My general supplement pattern would be to only take flavonoids and antioxidants on non-workout days or before ed after a workout, and senolytics could be during the complete fasts and possibly during some of the protein fasts. Don’t want too much too often. Maybe once a month?

ok I looked through all 320+ pub med entries that have the word fisetin in the title and cannot present all 141 of them that i saved so ill sned you a truncated list of …just the titles after this brief note….
Fisetin sounds like a wonder drug! it activites Sirt1 , it is a potent antiinflammatory, it protects all sorts of normal cells, it causes all kinds of cancer cells to self destruct…it is an AMPK pathway regulator, it is antidiabetic, anti depressant , it protects tisxsues against various kinds if injury, it is an antifungal, it prevents amyloid bujild up, it helps to treat parkinsons and als…and its activities are enhanced in conjunciton with mealtonin!>>>
Selected items
Items: 141
Select item 12107653
1.
Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1.

Do you agree that many of the effects you listed would be due to its direct or indirect antioxidant effects and not due to it functioning as a signaling agent since mammals do not make it and is not always available in food? Do you agree it seem reasonable that it is its antioxidant effects that is rescuing the senescent cells and either setting them up for apoptosis or for full return to functional competence as I described in my previous reply above?

It seems that the term “senolytic” leaves out the the removal of senescent cells that are truly rescued and return them to functional competence. Isn’t senescent cell rescue better than senescent cell death much of the time? When cells become senescent due to mitochondrial damage it seems that a powerful antioxidant such as fisetin could allow remaining mitochondria to reproduce/fuse and save the cell or if the percentage of good mitochondria is too small at least get enough of them to a level of competence that they can initiate successful apoptosis? Do you agree with this line of thinking or do you feel that fisetin has some direct ability to distinguish and kill senescent cells while leaving normal cells essentially alone?

Here\s one I found with bing>>> Fisetin treatment of preadipocytes reduced the phosphorylation of S6K1 and mTORC1 in a time- and concentration-dependent manner. To further our understanding of how fisetin negatively regulates mTORC1 signaling, we analyzed the phosphorylation of S6K1, mTOR and Akt in fisetin-treated TSC2-knockdown cells.

Here’s one where it protects bones via signalling>>As expected, the RANKL-activated p38 MAPK and JNKs signaling pathways were inhibited by fisetin in “shControl” cells (shCtrl); p38, JNK and c-jun were less phosphorylated in cells cultured in the presence of fisetin . However, fisetin had a lower inhibitory action in “shMKP-1” cells.

So the bottom line is somehow fisetin seems to activate pathways that protect good tissues and kills of bad actors like cancer cells It’s chemical structure looks very much like a DNA base pair and /or steroid hormone ..kind of like vitmain d3 And with all the OH’s sticking off of it it obvioudly has a lot of antioxidant potential..So my guess is it is causing good things by both ways acting as an antioxidant and a pseudo hormone that affects signalling

To prevent ageing one needs to choose a healthy lifestyle in their 20s or 30s or whenever possible, encompassing periodic fasting, eating small meals of predominantly raw, superfoods which include Fisetins and other phytonutrients, pre and probiotics, enzymes, minerals, and vitamins; a practice of daily aerobic movement where the heart is working against one’s weight–pushing against gravity (or the grave); meditation; projects that challenge the memory; quality, no stress relationships; and freedom to choose a life that is happy, peaceful, thrives in nature, grateful, vibrant and meaningful.

Taking a drug such as Fisetin to clear ageing cells to enhance autophagy might help, but is not the answer. The answer is to choose “life” every day, which encompasses the above factors over years, and prevents scrambling for the quick cure later. Unfortunately, most people get caught with too many symptoms, that have been ignored–many of which could have been attended to on the onset with natural therapies. Thus, becoming desperate to be fixed is the norm for a great many of people over 50.

I wonder if these senolytic drugs may synergize with short fasts of 3-5 days? I’m thinking here of Valter Longo’s work on the longevity and health benefits of his 5 day fading mimicking diet. Autophagy, apoptosis and stem cells are all upregulated which may make senescent cells more vulnerable?

However, I’ve looked through all of Valter Longo’s papers and don’t see any mention of senescent cells.Surprised that he hasn’t looked at that aspect yet!

I am no scientist and no doctor but I am almost 70 and have been coaching people on fasting programs with colonic irrigation for around 25 years; and I have to say I have seen people in their 40s, 50s, 60s, and 70s shed a great number of old cells as well as toxic material. This is not the fasting mimicking diet. This is the real thing–no food at all, just mineral water, coconut water and mineral broth. After 7 days and some 10 or 20 days, those who come with inflammatory health conditions leave feeling and looking vibrantly healthy. Autophagy, apoptosis, mitophagy, lymphophagy, you see it all. And what a miraculous privlege it is!.

Eliminating senscent cells requires a daily practice, a whole lifestyle, a commitment to eliminate that which contributes to ageing and all that sustains, enhances, uplifts and enlightens your existence. This includes intermittent and periodic fasting and list of other practices–I did mention some of them in my last comment post. . . Hillary

One is that over the past year research is showing a more complex picture of the role of inflammation and senescence. It is now becoming clear that some degree of inflammation and the SASP is necessary for repair and rejuvention, but obviously not to excess, but the goal is careful intervention with senolytics and I don’t feel that we’re at that point yet. Our knowledge is emerging but still very rudimentary.

This is also true about toxicity. We do not know that fisetin is safe at very high doses. The quinolone antibiotics are given generally over a short course and are associated with spontaneous tendon ruptures. This is almost certainly due to topoisomerase inhibition.

The thing is, even though the SASP is required for regeneration, the persistance of these cells shows that this regeneration has not occurred, otherwise they would have been replaced with healthy tissue. So I’m not concerned about losing the transient benefits of senescent cells. They are useful and used rather than apoptosis in those situations when a chunk of tissue needs to be arrested and replaced – but this situation should not persist.

Whether they can be removed safely in the very old is a bigger concern for me. As is the long term effect of forcing your remaining cells to replace them (bringing those cells closer to senescence, on average).

But as there are clinical trials on fisetin in humans going on RIGHT NOW, most of us can surely afford to wait.

I would recommend you research the iodine protocol. Iodine allows apoptosis to occur. People are taking huge doses (many hundreds of times the RDA) and reporting many benefits. At least Google apoptosis and iodine.

I do 3-4 5 day dry fasts during the year to increase autophagy and get rid of sentient cells, I wonder if taking scenolytics would help this process.
I also do intermittent fasting and thinking of using senolycs with that as well, anyone have any experience with this?

Senolytics have become one of the most hopeful near-term interventions for aging. Not sure it’s much use to me as I’m only 34 and have been doing CR since I was 18, but great for older people. Although, I’m much more excited about companies like Unity, who are working on more powerful senolytics. After following life extension for over 15 years, things are finally starting to pick up momentum. We just a win or two for aging therapies (like senolytics) and it’ll encourage even more investment.

I’m producing 98% pure Fisetin from a novel botanical source and presently have 20 kilos per month capacity. Planning to scale this to 1,000 kilos per month in one year. Im personally going to take 500 Mgs. once per week.

Piperlonggumine is much easier due to centuries of use in Ayurveda. I manufactured industrial scale quantities of Phytochemicals for 18 years and have zero concerns about safety. Supply is no problem and I’m taking 300 mgs. of this with the Fisetin while research on dose / efficacy continues.

Why not take the study dose ( being conducted now) ?
1200 mg for each of 2 days, repeat 1 month later.
Do annually.
Or base it on rat data and do 500 mg, for 5 nights, that’s it.
To enhance effect, water fast on dosing days.
Maybe add a dose of Life Extensions new bioavailable Quercetin plus black tea Senolyic product.